DESCRIPTION (adapted from the applicants' abstract) In the premature infant, the ductus arteriosus frequently remains open for many days or weeks after delivery. A persistent patent ductus arteriosus is associated with significant morbidity: bronchopulmonary dysplasia with its prolonged need for mechanical ventilation. Numerous studies have shown that early closure of the ductus arteriosus decreases the severity of bronchopulmonary dysplasia. Although inhibitors of prostaglandin syntheses, like indomethacin, induce ductus closure in 85 percent of preterm infants in whom they are used, ductus reopening occurs in 20 to 100 percent of treated infants. The studies proposed in this application will examine the mechanisms involved in early, spontaneous ductus closure in the full-term newborn and those involved in the delayed closure of the premature newborn. They will also examine the mechanisms involved in the high rate of ductus reopening after indomethacin-induced closure. They will use the premature baboon model of persistent patent ductus arteriosus, which is the only model that mimics the long-term events surrounding ductus patency in the preterm human. These studies will examine the hypothesis that hypoxia produced within the wall of the ductus arteriosus, after birth, initiates the changes in growth factors, cell receptors, matrix elements, and vasoregulators that cause permanent and irreversible ductus closure. They will use immunohistochemical and in situ hybridization techniques to study the changes in mRNA and protein expression of these factors. They will use isolated organ perfusion techniques to examine the changes in vasoregulatory tone. These studies should increase our understanding of what initiates and sustains the process of ductus closure after birth and why it does not occur in the preterm infant.